Organocatalytic process for asymmetric synthesis of decanolides

ABSTRACT

The present invention discloses organocatalytic process for asymmetric synthesis of highly enantioselective decanolide compounds in high yield with &gt;99% ee. Further, the present invention disclose cost effective, improved organocatalytic process for asymmetric synthesis of highly enantioselective decanolides compounds from non-chiral, cheap, easily available raw materials.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional and claims the benefit of priority ofU.S. application Ser. No. 14/426,305, filed 5 Mar. 2015, which is a U.S.National Stage Filing under 35 U.S.C. §371 from InternationalApplication No. PCT/IN2013/000542, filed on 6 Sep. 2013, and publishedas WO2014/037964 on 13 Mar. 2014, which application claims the benefitof priority to Indian Application No. 2765/DEL/2012, filed on 6 Sep.2012; which applications and publication are incorporated herein byreference and made a part hereof in their entirety, and the benefit ofpriority of each of which is claimed herein.

TECHNICAL FIELD

The present invention provides organocatalytic process for asymmetricsynthesis of highly enantioselective decanolide compounds in high yieldwith >99% ee.

Further present invention provides cost effective, improvedorganocatalytic process for asymmetric synthesis of highlyenantioselective decanolides compounds from non-chiral, cheap, easilyavailable raw materials.

BACKGROUND AND PRIOR ART

Decanolides, isolated from various fungal metabolites have attractedconsiderable attention due to the interesting biological properties andscare availability of macrolides. Aspinolide A, its diastereomerStagonoide F, Stagonolide C, Stagonolide E and several other decanolideshave been isolated from cultures of various fungii. Few syntheses ofthese important Macrolides are known most of which involves the use ofkinetic resolution for generating chirality or based on chiral poolapproach involving large number of steps.

T. Mahapatra et al. in Bull. Chem. Soc. Jpn., 2011, 84 (5), 511-519describes efficient asymmetric synthesis of naturally occurring smallring macrolide, stagonolide-D and stagonolide-G from (S)-ethyl lactateas a chiral pool. Further a convergent and efficient total synthesis ofstagonolide C exploits the high configuration control in the Prinscyclization along with alkene rearrangement and ring-closing metathesisas key steps is reported. in Helvetica Chimica Acta. 95 (2) 227-324February 2012 by Jhillu S. Yadav et al. The nonenolides such asStagonolides G to Stagonolides I and Modiolide A are disclosed in J.Nat. Prod., 2008, 71 (11), 1897-1901. The stereoselective totalsynthesis of Stagonolide G is disclosed in Tetrahedron Letters, 51 (21)2010, 2903-2905.

The stereoselective total synthesis of the nonenolide, (+)-stagonolide Binvolves epoxide homologation, hydrolytic kinetic resolution andring-closing metathesis is described in Synthesis 2010(6): 1039-1045.

Tetrahedron Letters 53, (2) January 2012, 256-258 discloseschemoenzymatic asymmetric total synthesis of small ring macrolidestagonolide-E comprises ruthenium(II), enzyme combo dynamic kineticresolution reaction, whereas Synlett 2009 (18) 2924-2926 describesstereoselective total synthesis of (−)-(6R,11R,14R)-Colletallolcomprises Jacobsen's hydrolytic kinetic resolution (HKR) andring-closing metathesis protocol.

Further the synthesis of 9-membered macrolide, stagonolide-F (3),wherein Jacobsen's hydrolytic kinetic resolution (HKR) and Sharplessepoxidation is used for the creation of two stereogenic centers isreported in Bioorganic Chemistry 37 (2), 2009, 46-51.

Tetrahedron Letters 53, (9), February 2012, 1153-1155 discloses totalsynthesis of stagonolide C using chiral pool strategy. Novel synthesisof putaminoxin, stagonolide-F and aspinolide-A have been achieved byutilizing (S) and (R)-malic acid is known from Letters in OrganicChemistry, 8, (2), February 2011, 143-149 (7).

In view of foregoing most of the process in the prior art involveschiral pool strategy, use of expensive and toxic metal catalyst, alsogives poor yield and entioselectivity of desired decanolides ornonenolides. Further, the lengthy steps in the prior art impact theoverall yield of the decanolides.

The present inventors therefore felt a need to develop enantioselectivesynthesis of biologically active natural product based on asymmetricorganocatalysis by a simple, concise and flexible route with reducednumber of process steps using non chiral, cheaper, easily availablestarting material.

OBJECT OF INVENTION

The main objective of the present invention is to provide cost-effectiveand improved organocatalytic process for asymmetric synthesis of highlyenantioselective decanolide compounds.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an organo catalytic processfor preparation of decanolides of Formula Ia with highenantioselectivity,

-   -   wherein, R1, R2, R3 and R4 are independently selected from the        group consisting of H, OH, substituted or un substituted (C₁-C₅)        alkyl; or R2 and R3 may together form an epoxy ring; (-----)        represents either single or double bond, (        ) represents cis or trans position of the substituents R1 to R4        i.e. (either        or        ); wherein the said process comprising the steps of;    -   i. enantioselective allylboration of aldehyde (1) in presence of        allyldiisopinocamphenylborane at temperature in the range of        −120° C. to −80° C. for 1-2 hrs in non-polar organic solvents        selected from diethyl ether, pentane, cyclopentane, benzene,        toluene, 1,4-dioxane, chloroform or mixtures thereof followed by        treatment with NaOH and aqueous H₂O₂ to obtain chiral allylic        alcohol (3);    -   ii. protecting chiral allylic alcohol (3) as obtained in        step (i) with TBS by treating with TBSCl, imidazole, in a polar        aprotic solvents selected from DMF, DCM, THF, ethyl acetate,        acetone, DMSO to obtain compound (4) followed by Wittig reaction        by reacting Wittig reagent. Ph₃P═CHCO₂Et in a polar aprotic        solvents preferably THF to obtain corresponding α-β unsaturated        ester (5);    -   iii. reducing α-β unsaturated ester (5) as obtained in step (ii)        in presence of DIBAL-H in toluene at temperature range −80° C.        to −50° C. to obtain α,β-unsaturated aldehyde (6) followed by        organocatalytic Jørgensen epoxidation of α,β-unsaturated        aldehyde (6) in presence of a chiral bisaryl-silyl-protected        pyrrolidine preferably        bis(3,5-bis(trifluoromethyl)phenyl)trimethyl silyloxy)        methyl]pyrrolidine in the range of 5% to 20% and hydrogen        peroxide and polar aprotic solvents selected from DMF, DCM, THF,        ethyl acetate, acetone, DMSO at ambient temperature ranging        between 25-35° C. for a period followed by reduction in presence        of NaBH₄ in lower alcohol selected from methanol, ethanol,        n-propanol, iso-propanol, n-butanol at temperature range −5° C.        to 5° C. to obtain enantiomerically enriched epoxy alcohol        compound (7);    -   iv. stirring epoxy alcohol (7) in presence of        triphenylphosphine, iodine and imidazole reagent in an organic        solvent selected from the group consisting of diethyl ether,        DMF, DCM, THF, ethyl acetate, acetone, acetonitrile, methanol,        ethanol or mixtures thereof followed by treatment with Zn and        NaI in methanol to obtain allylic alcohol (9) and further        protecting allylic alcohol (9) with MOM in presence of MOMCl,        DIPEA in DCM solvent to obtain compound (10) followed by        deprotection of TBS to afford MOM protected allylic alcohol        (11);    -   v. esterification of MOM protected allylic alcohol (11) with MOM        protected carboxylic acid compound (12) in presence of EDCl and        DMAP in a polar solvent DCM to obtain ester compound (13); and        ring-closing metathesis of ester compound (13) with Grubbs        second generation carbene complex, followed by deprotection of        MOM to obtain Formula Ia.

In one embodiment of the present invention compound of Formula Ia isselected from the group of Stagonolide C or Modiolide A.

In an embodiment of the present invention an organo catalytic processfor preparation of decanolides of Formula Ib with highenantioselectivity

wherein, R1 and R2 are independently selected from —OH or —H,substituted or un-substituted (C₁-C₅) alkyl; (

) bond represents either cis or trans position of the R1 and R2 i.e.(either

or

).

-   -   with the proviso, when R1 is —OH either in cis or trans        position; R2 is methyl group either in cis or trans position;    -   wherein, the said process comprising the steps of;        -   i. protecting one of the terminal hydroxyl group of            diol (21) with benzyl group by using benzyl bromide in dry            THF to obtain corresponding mono-benzyl ether (22), followed            by TEMPO catalyzed oxidation in presence of iodobenzene            diacetate in organic solvent selected from DCM, DMF to            obtain benzyl protected aldehyde (23);        -   ii. proline-catalyzed direct asymmetric α-aminoxylation of            benzyl protected aldehyde (23) using nitrosobenzene in            acetonitrile as an oxygen source, followed by treatment with            NaBH₄ in methanol further treating with copper (II) acetate            in methanol for 24 hrs (10-20 mins) at temperature ranging            between to obtain chiral diol (24), which is further treated            with dibutyl tin oxide and tosyl chloride, triethylamine in            DCM furnishes the mono tosylated compound, which is further            treated with potassium carbonate in dry methanol at 0-25° C.            for 20-40 mins to obtain epoxy compound (25);        -   iii. reducing epoxy compound (25) in presence of LAH to            chiral secondary alcohol (26), subsequently protecting with            TBS by using TBS-Cl, imidazole in DCM followed by            deprotection of benzyl in presence of palladium catalyzed            reduction in ethyl acetate gives TBS protected alcohol (28);            followed by TEMPO catalyzed oxidization in presence of            iodobenzene diacetate in organic solvent preferably DCM to            obtain aldehyde compound (29);        -   iv. catalytic Horner-Wadsworth-Emmons olefinating and            concomitant copper catalyzed oxidizing of compound (29) to            yield hydroxyl ester (30), further protecting with MOM in            presence of MOMCl and DIPEA in DCM to corresponding            protected ester (31);        -   v. reducing the protected ester (31) using DIBAL-H in dry            DCM at temperature range from −70° C. to −85° C. to obtain            aldehyde (32), followed by Wittig reaction in dry THF at            temperature range from −70° C. to −85° C. to obtain            corresponding ester (33); further deprotecting of TBS in            presence of TBAF in THF to secondary alcohol (34), followed            by alkali hydrolysis of the ester with LiOH in methanol and            water to carboxylic acid (35); and        -   vi. yamaguchi macrolactonizing of (35) in presence of 2,4,6            trichloro benzoyl chloride and triethylamine in THF and DMAP            in toluene to obtain the MOM protected decanolide (36)            subsequently deprotecting of MOM to obtain decanolides of            Formula Ib.

In another embodiment of the present invention the decanolides ofFormula Ib is

In another embodiment of the present invention an organo catalyticprocess for the preparation of decanolides of Formula Ic with highenantioselectivity

-   -   wherein R1 and R2 is independently selected from the group        consisting of H, OH, substituted or unsubstituted (C₁-C₅) alkyl;        (        ) represents cis or trans position of R1 and R2 i.e. (either        or        )    -   with the proviso, when, R1 is methyl either in cis or trans        position; R2 is —OH on the same position with regard to R1    -   wherein the said process comprising the steps of;        -   i. enantioselective allylboration of aldehyde (1) in            presence of allyldiisopinocamphenylborane at temperature in            the range of −120° C. to −80° C. for 1-2 hrs in non-polar            organic solvents selected from diethyl ether, pentane,            cyclopentane, benzene, toluene, 1,4-dioxane, chloroform or            mixtures thereof followed by treatment with NaOH and aqueous            H₂O₂ to obtain chiral allylic alcohol (3);        -   ii. esterification of allylic alcohol (3) with TBS protected            carboxylic acid (15) in presence of EDCl HCl, DMAP in DCM at            temperature range 0° to 30° C. for 5 to 8 hrs with            subsequent deprotection of TBS in presence of TBAF in THF            for 6-8 hrs yields allylic alcohol (17); and        -   iii. ring closing metathesis reaction of compound (17) in            presence of Grubbs II catalyst (5 to 15%) in dry DCM for            18-24 hrs to obtain decanolides of Formula Ic

In yet another embodiment of the present invention decanolides ofFormula Ic is Aspinolide A.

In still another embodiment of the present invention MOM protectedcarboxylic acid used in step (v) and (ii) respectively is obtained bysaid process comprising;

-   -   i. protecting one of the hydroxyl group of 1,2 diol with TBS in        presence of TBS-Cl, imidazole in polar organic solvent selected        from DCM, DMF, THF, ethyl acetate, acetone, DMSO at temperature        range 0° C. to 30° C. for 5-8 hrs to give mono TBS substituted        alcohol further subjecting the alcohol (2a) to TEMPO catalyzed        oxidation in presence of iodobenzene diacetate in polar organic        solvent such as DCM at temperature range 20° C. to 30° C.        followed by Wittig olefination with Ph₃P═CHCOOEt in THF at        ambient temperature ranging between 25-35° C. for 10-15 hrs        results in olefin ester;    -   ii. reducing olefin ester (3a) using DIBAL-H in toluene at        temperature −80° C. to −60° C. for 0.5 to 2 hrs to obtain        protected aldehyde;    -   iii. subjecting protected aldehyde of step (ii) to epoxidation        in presence of a chiral bisaryl-silyl-protected pyrrolidine in        the range of 5% to 20% at ambient temperature to        enantiomerically enriched epoxy alcohol;    -   iv. converting epoxy alcohol of step (iii) into epoxy iodide in        presence of iodine-triphenylphosphine-imidazole reagent in an        organic solvent selected from diethyl ether, DMF, DCM, THF,        ethyl acetate, acetone, acetonitrile, methanol, ethanol or        mixtures thereof under reflux for 2-4 hrs with Zn and NaI to        obtain allylic alcohol;    -   v. protecting chiral hydroxy group of alcohol of step (iv) with        MOM in presence of -MOMCl, DIPEA in DCM as solvent to obtain TBS        ether followed by deprotection with CSA in methanol at ambient        temperature in 5-10 mins to compound;    -   vi. oxidizing compound of step (v) using iodobenzene diacetate        and TEMPO, in presence of water miscible polar organic solvent        preferably acetonitrile to obtain chiral protected carboxylic        acid;    -   vii. or optionally chiral protected carboxylic acid is obtained        by protecting one of the hydroxyl group of 1,2 diol with TBS in        presence of TBS-Cl, imidazole in polar organic solvent selected        from DCM, DMF, THF, ethyl acetate, acetone, DMSO at temperature        range of 0° C. to 30° C. for 5-8 hrs to give mono TBS        substituted alcohol and subjecting to TEMPO catalyzed oxidation        in presence of iodobenzene diacetate in polar organic solvent        selected from DCM at room temperature for 1-2 hrs to obtain        protected aldehyde;    -   viii. α-hydroxylation of aldehyde of step (vii) in presence of        proline using nitrosobenzene in acetonitrile at temperature in        the range of −25° C. to −10° C. for 20-30 hrs followed by        in-situ reduction of hydroxyl aldehyde and treating with        copper(II)acetate in methanol to obtain corresponding chiral        diol;    -   ix. selective tosylation of chiral diol of step (viii) using        tosyl chloride, triethylamine, and catalytic amount of        dibutyltin oxide (Bu₂SnO) in DMAP furnishes the mono tosylated        compound, further treating with potassium carbonate in dry        methanol at 0° C.-25° C. for 20-40 mins to obtain the epoxide        followed by ring closure in presence of base to epoxide and        converting to allylic alcohol by refluxing in the presence of        12, Imidazole, CH₃CN, diethyl ether, NaI, Zn and MeOH;    -   x. protecting allylic alcohol of step (ix) with MOM by using        MOMCl, DIPEA in DCM as solvent and deprotecting alcohol with CSA        in methanol at ambient temperature ranging between 25-35° C. in        5-10 mins and subjecting alcohol to TEMPO catalyzed oxidation        using iodobenzene diacetate in presence of water miscible polar        organic solvent such as methanol, acetonitrile preferably        mixture of ACN:water in (4:1) ratio at room temperature        25-35° C. for 3 to 4 hrs to obtain chiral protected carboxylic        acid.

In still another embodiment of the present invention enantioselectivityof compound of formula Ia, formula Ib and formula Ic is in the range of98-99%.

In still another embodiment of the present invention yield of compoundof formula Ia, formula Ib and formula Ic is in the range of 20-35%.

In still another embodiment of the present invention yield of MOMprotected carboxylic acid is in the range of 50-98%.

In still another embodiment of the present invention chirality isintroduced in the said compounds in process steps of proline catalyzedasymmetric α-aminoxylation and/or epoxidation of aldehydes.

DETAILED DESCRIPTION

The invention will now be described in detail in connection with certainpreferred and optional embodiments, so that various aspects thereof maybe more fully understood and appreciated.

Abbreviations

Bu₂SnO: Dibutyltin oxide

CSA: Camphorsulfonic acid

DMAP: 4-Dimethylaminopyridine

DMSO: Dimethyl sulfoxide

DIBAL-H: Diisobutylaluminium hydride

DIPEA: N,N-Diisopropylethylamine

EDCl: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

MOM: Methoxy methyl ether

NaBH₄: Sodium borohydride

Et₃N: Triethylamine

Ph₃PCH₃I: methyiodideltriphenylphosphonium (Wittig reagent)

PhNO: Nirosophenyl

Ph₃P═CHCO₂Et: ethyl triphenyiphosphoranylidene acetate

[Ru(BINAP)Cl₂]: Ru-diphosphine complexes

BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

TBAF: Tetra-n-butylammonium fluoride

TBS: tert-butyldimethylsilyl

TEMPO: (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl, or(2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl

THF: Tetrahydrofuran

The present invention in pursuit of developing a concise method forsynthesis of biologically active natural compounds of the groupdecanolides with high enantioselectivity i.e. >99% provides organocatalyzed asymmetric synthesis of decanolides. The said process issimple, flexible with reduced number of steps. The inventive feature inthe instant process lies in the use of process steps such as prolinecatalyzed asymmetric α-aminoxylation and Jorgensen's epoxidation ofaldehydes for introduction of chirality to obtain chiral intermediatesthat can lead to formation of said chiral decanolides thus making theprocess highly selective with specificity towards enatio selectivityusually >99% and with increased yields. Further the use of orgnocatalystmakes the process environmentally feasible and cost effective.

In preferred embodiment, the present invention provides cost-effective,non-toxic, organocatalytic process for the asymmetric synthesis ofhighly enantioselective decanolides compounds with more than 99% ee

In preferred embodiment, the present invention provides organocatalyticprocess for the asymmetric synthesis of decanolide compounds havingFormula Ia;

wherein, R1, R2, R3 and R4 is independently selected from the groupconsisting of H, OH, substituted or un substituted (C₁-C₅) alkyl; or R2and R3 may together form an epoxy ring; (-----) represents either singleor double bond, (

) represents cis or trans position of the substituents R1 to R4 i.e.(either

or

);with the proviso, when R1, R2 and R3 is —OH either in cis or transposition; R4 represents n-propyl either in cis or trans position; thecompound is Stagonolide-B;

with the proviso, when R1 and R2 is —OH either in cis or trans position;R4 represents methyl either in cis or trans position; the compound isStagonolides-C; and

with the proviso, when R1 is —OH either in cis or trans position; R2 andR3 is together form epoxy ring either in cis or trans position; R4represents methyl either in cis or trans position; the compound isStagonolides-D; and

with the proviso, when R1 and R2 is —OH either in cis or trans position;R4 represents methyl group either in cis or trans position; the compoundis Modiolide-A;

In a preferred embodiment, the present invention provides anorganocatalytic process for the preparation of compound of Formula Ia;preferably Stagonolide C or Modiolide A (as shown in Scheme 1)comprising;

-   a) enantioselective allylboration of aldehyde (1) to obtain allylic    alcohol (3), protected with TBS to obtain compound (4), followed by    Wittig reaction to obtain corresponding ester (5);-   b) reduction of ester (5) in presence of DIBAL-H to obtain aldehyde    (6), followed by epoxidation to yield enantiomerically enriched    epoxy alcohol (7);-   c) conversion of compound (7) to allylic alcohol (9) in presence of    triphenylphosphine, iodine and imidazole reagent followed by    treatment with Zn and NaI in alcohol, and further protection with    MOM to obtain compound (10) followed by deprotection of TBS to    afford alcohol (11);-   d) esterification of MOM protected allylic alcohol (11) with    carboxylic acid compound (12) to obtain ester compound (13); and-   e) ring-closing metathesis of ester compound (13), followed by    deprotection of MOM to yield the desired dacanolides; Stagonolide C    or Modiolide A.

In accordance with scheme 1, the aldehyde compound (1) undergoesenantioselective allylboration in presence ofallyldiisopinocamphenylborane at temperature in the range of −120° C. to−80° C. for 1-2 hrs in non-polar organic solvents such as, diethylether, pentane, cyclopentane, benzene, toluene, 1,4-dioxane, chloroformor mixtures thereof; preferably mixture of diethyl ether-pentane,followed by treatment with NaOH and aqueous H₂O₂ to obtain chiralallylic alcohol (3) in 75% yield with 99% ee. Further the sec alcoholcompound (3) is protected with TBS group by treating with TBSCl,imidazole, in suitable polar aprotic solvents such as DMF, DCM, THF,ethyl acetate, acetone, DMSO etc. gives protected compound (4) which isfurther treated with Wittig reagent i.e. Ph₃P=CHCO₂Et in suitable polaraprotic solvents to get α-β unsaturated ester (5). The reduction ofester (5) gives α,β-unsaturated aldehyde (6) in presence of DIBAL-H intoluene at temperature range −80° C. to −50° C. Further the asymmetricorganocatalytic Jørgensen epoxidation of α,β-unsaturated aldehydes withhydrogen peroxide in polar aprotic solvents such as DMF, DCM, THF, ethylacetate, acetone, DMSO etc. affords enantiomerically enriched epoxyalcohol (7), wherein the Jorgensen epoxidation takes place in presenceof a chiral bisaryl-silyl-protected pyrrolidine; preferablybis(3,5-bis(trifluoromethyl)phenyl)trimethyl silyloxy)methyl]pyrrolidine having molar concentration in the range of 5% to 20%at ambient temperature followed by reduction in presence of NaBH₄ inlower alcohol such as methanol, ethanol, n-propanol, iso-propanol,n-butanol at temperature range −5° C. to 5° C. The obtained epoxyalcohol (7) is thus converted into epoxy iodide in presence ofiodine-triphenylphosphine-imidazole reagent in suitable organic solventsuch as diethyl ether, DMF, DCM, THF, ethyl acetate, acetone,acetonitrile, methanol, ethanol or mixtures thereof; preferably mixtureof diethyl ether and acetonitrile in (3:1) ratio, which is furtherrefluxed with Zn and NaI in MeOH affords the secondary allylic alcohol(9), subsequent protection with MOM in presence of MOMCl, DIPEA in DCMsolvent followed by deprotection of TBS gives the MOM protected allylicalcohol (11).

Further the alcohol (11) is esterified in presence of EDCl and DMAP insuitable polar solvent such as DCM with MOM protected carboxylic acid(12) to get ester (13) in 86% yield, wherein carboxylic acid (12) issynthesized by different methods. The obtained ester (13) is thensubjected to ring closing metathesis reaction with Grubbs secondgeneration carbene complex to obtain MOM protected decanolides (14)which is further deprotected gives desired decanolides, such asStagonolide C or Modiolide A (from Stagonolide C Modiolide A can besynthesized in two steps by literature known procedure).

In another embodiment, the MOM protected carboxylic acid (12) can besynthesized by two methods. The first method for the preparation of MOMprotected carboxylic acid (12) is illustrated in scheme 2.

In accordance with scheme 2, the 1,4 diol (1a) is protected with TBS inpresence of TBS-Cl, imidazole in polar organic solvent such as DCM, DMF,THF, ethyl acetate, acetone, DMSO at temperature range 0° C. to 30° C.for 5-8 hrs to give mono TBS substituted alcohol (2a) in 66% yield.Further the alcohol (2a) is subjected to TEMPO catalyzed oxidation inpresence of iodobenzene diacetate in polar organic solvent such as DCMat temperature range 20° C. to 30° C. followed by Wittig olefinationwith Ph₃P═CHCOOEt in THF at ambient temperature for 10-15 hrs results inolefin ester (3a) in 93% yield. Further the reduction of olefin ester(3a) using DIBAL-H in toluene at temperature −80° C. to −60° C. for 0.5to 2 hrs gives 73% yield of olefin aldehyde (4a). The asymmetricorganocatalytic Jorgensen epoxidation of (4a) affords enantiomericallyenriched epoxy alcohol (5a) in 53% yield, followed by reduction inpresence of NaBH₄ in lower alcohol such as methanol, ethanol,n-propanol, iso-propanol, n-butanol at temperature range −5° C. to 5° C.for 0.5 to 2 hrs. The obtained epoxy alcohol (5a) is thus converted intoepoxy iodide in presence of iodine-triphenylphosphine-imidazole reagentin suitable organic solvent such as diethyl ether, DMF, DCM, THF, ethylacetate, acetone, acetonitrile, methanol, ethanol or mixtures thereof;preferably mixture of diethyl ether and acetonitrile in (3:1) ratio,which under reflux for 2-4 hrs with Zn and NaI in MeOH affords thesecondary allylic alcohol (6a) in 90% yield, subsequently the hydroxylgroup of (6a) is protected with MOM in presence of -MOMCl, DIPEA, r.t inDCM as solvent to afford primary TBS ether (7a), which is selectivelycleaved with CSA in methanol at ambient temperature in 5-10 mins toafford alcohol (8a) in 63% yield. Further the oxidation of alcohols (8a)using iodobenzene diacetate and TEMPO, in presence of water misciblepolar organic solvent such as methanol, acetonitrile (ACN); preferablymixture of ACN:water in (4:1) ratio at room temperature for 3 to 4 hrsto obtain MOM protected carboxylic acid (12) in 80% yield, whereinaddition of a trace of water is found to be crucial for completeconversion of alcohol into corresponding acid (12).

Alternately, the second method for the preparation of MOM protectedcarboxylic acid (12) is illustrated in scheme 3.

In accordance with scheme 3, the 1,4 diol (1a) is protected with TBS inpresence of TBS-Cl, imidazole in polar organic solvent such as DCM, DMF,THF, ethyl acetate, acetone, DMSO at temperature range of 0° C. to 30°C. for 5-8 hrs to give mono TBS substituted alcohol (2a) in 76% yield.Further the alcohol (2a) is subjected to TEMPO catalyzed oxidation inpresence of iodobenzene diacetate in polar organic solvent such as DCMat room temperature for 1-2 hrs to obtain aldehyde (3b) in 85% yield,further (3b) is exposed to proline-catalyzed α-hydroxylation protocolusing nitrosobenzene in acetonitrile at temperature range of −25° C. to−10° C. for 20-30 hrs, followed by the in situ reduction of theresultant hydroxy aldehyde using sodium borohydride (NaBH₄) in methanol,further obtained compound is treated with copper(II)acetate in methanolwhich provides the corresponding chiral diol (4b) in 67% yield. Theselective tosylation of the diol (4b) using tosyl chloride,triethylamine, and catalytic amount of dibutyltin oxide (Bu₂SnO) in DMAPfurnishes the mono tosylated compound, which is further treated withpotassium carbonate in dry methanol at 0° C. for 20-40 mins to obtainthe epoxide (5b) in 92% yield. The epoxide is then converted intoallylic alcohol (6a) by refluxing in the presence of 12, Imidazole,CH₃CN, diethyl ether, NaI, Zn and MeOH. The hydroxyl group of (6a) isprotected with MOM by using MOMCl, DIPEA, rt in DCM as solvent. Furtherthe primary TBS ether (7a) is selectively cleaved with CSA in methanolat ambient temperature in 5-10 mins yields alcohol (8a) in 63%. FurtherTEMPO catalyzed oxidation of alcohol (8a) using iodobenzene diacetate inpresence of water miscible polar organic solvent such as methanol,acetonitrile (ACN); preferably mixture of ACN:water in (4:1) ratio atroom temperature for 3 to 4 hrs is carried to obtain MOM protectedcarboxylic acid (12) in 80% yield.

The carboxylic acid (12) obtained from the above two methods is furtherused for the preparation of desired decanolides; preferably StagonolideC or Modiolide A as described hereinabove.

In another preferred embodiment, the present invention providesorganocatalytic process for the asymmetric synthesis of decanolides ofFormula Ib.

wherein, R1 and R2 are independently selected from —OH or —H,substituted or un-substituted (C₁-C₅) alkyl; (

) bond represents either cis or trans position of the R1 and R2 i.e.(either

or

).with the proviso, when R1 is —OH either in cis or trans position; R2 ismethyl group either in cis or trans position the compound is StagonolideE.

In yet another embodiment the process for the preparation of compound ofFormula Ib, preferably Stagonolides E (as shown in scheme 4) comprisesthe steps of:

-   -   a) protecting one of the terminal hydroxyl group of diol (21) to        obtain corresponding mono-benzyl ether (22), followed by        oxidation to give benzyl protected aldehyde (23);    -   b) proline catalyzed asymmetric aminoxylating of (23) to obtain        chiral diol (24), which is further treated with dibutyl tin        oxide and tosyl chloride with subsequent alkaline hydrolysis to        give epoxy compound (25);    -   c) reducing epoxy compound (25) in presence of LAH affords        chiral secondary alcohol (26), subsequent protecting with TBS        followed by deprotection of benzyl gives alcohol (28); further        TEMPO catalyzed oxidizing affords aldehyde compound (29);    -   d) catalytic HWE olefinating and concomitant copper catalyzed        oxidizing of compound (29) gives hydroxyl ester (30), further        protecting with MOM gives corresponding protected ester (31);    -   e) reducing the protected ester (31) to obtain aldehyde (32),        followed by Wittig reaction gives corresponding ester (33);        further deprotecting of TBS gives secondary alcohol (34),        followed by alkali hydrolysis yields corresponding carboxylic        acid (35); and    -   f) macrolactonizing of (35) in presence of 2,4,6 trichloro        benzoyl chloride, with subsequent deprotecting of MOM gives        desired decanolide compound, preferably Stagonolide E.

In accordance with scheme 4, the substrate 1,6 diol (21) is protectedwith benzyl group by using benzyl bromide in dry THF to obtainmono-benzyl ether (22), subsequently undergoes to TEMPO catalyzedoxidation in presence of iodobenzene diacetate in organic solvent suchas DCM, DMF, affords aldehyde (23). Further the obtained aldehyde onproline-catalyzed direct asymmetric α-aminoxylation using nitrosobenzenein acetonitrile as an oxygen source, followed by treatment with NaBH₄ inmethanol affords intermediate compound; further obtained compound istreated with copper (II) acetate in methanol for 24 hrs gives thecorresponding chiral diol (24). The selective tosylation of the diol(24) using tosyl chloride, triethylamine, and catalytic amount ofdibutyltin oxide (Bu₂SnO) in DCM furnishes the mono tosylated compound,which is further treated with potassium carbonate in dry methanol at 0°C. for 20-40 mins gives the epoxide (25). Further the epoxide is treatedwith LAH in dry ether to afford chiral secondary alcohol (26),subsequently the hydroxyl group of (26) is protected by TBS by usingTBS-Cl, imidazole in DCM to obtain compound (27), the benzyl group isfurther cleaved in presence of palladium catalyzed reduction in ethylacetate gives TBS protected alcohol (28). The obtained alcohol on TEMPOcatalyzed oxidation in presence of iodobenzene diacetate in organicsolvent yields aldehyde (29). Further the α-aminoxylation of aldehyde(29), is carried out using nitrosobenzene as the electrophilic componentfollowed by in situ Horner-Wadsworth-Emmons olefination with DBU as basethat furnishes anilinoxy olefinic ester. The deprotection of anilinoxygroup to hydroxyl group is achieved with Cu(OAc)₂ in ethanol givesolefin ester (30), further protecting hydroxyl group of (30) in presenceof MOMCl and DIPEA in DCM furnishes ester (31). The ester thus formed onreduction by using DIBAL-H in dry DCM at temperature range from −70° C.to −85° C. affords corresponding aldehyde (32), the obtained aldehyde onWittig reaction in dry THF at temperature range from −70° C. to −85° C.forms ester (33). The TBS group is further cleaved in presence of TBAFin THF to afford (34). Subsequently, hydrolysis of the ester with LiOHin methanol and water yields the corresponding carboxylic acid (35). Theacid is further subjected to Yamaguchi macrolactonization conditionsi.e. acid (35) is treated with 2,4,6-trichlorobenzoyl chloride andtriethylamine in THF, reflux with DMAP, in toluene to afford the MOMprotected decanolide (36) further the deprotection of MOM group giverise to desired decanolides i.e Stagonolide-E in high yield, 40% overalland purity, 98% enantiomeric purity.

In yet another embodiment, the present invention providesorganocatalytic process for the asymmetric synthesis of 12 member ringmacrolide; preferably (6R,11R,14R)-colletallol (as shown in Scheme 4a)which comprises Yamaguchi cyclization of compound (37) and (38) inpresence of 2,4,6 trichloro benzoyl chloride, with subsequentdeprotecting of MOM and TBS group under the condition as describedhereinabove gives desired 12 member ring macrolide i.e. (6R,11R,14R)Colletallol.

In another preferred embodiment, the present invention providesorganocatalytic process for the asymmetric synthesis of decanolides ofFormula Ic.

wherein, R1 and R2 is independently selected from the group consistingof H, OH, substituted or unsubstituted (C₁-C₅) alkyl; (

) represents cis or trans position of R1 and R2 i.e. (either

or

);with the proviso, when, R1 is methyl either in cis or trans position; R2is —OH on the opposite position with regard to R1 the compound isStagonolide-F; and

with the proviso, when, R1 is methyl either in cis or trans position; R2is —OH on the same position with regard to R1 the compound is AspinolideA; and

In yet another embodiment, the present invention providesorganocatalytic process for the preparation of compound of Formula Ic,preferably Stagonolide F and Aspinolide A (as shown in scheme 5)comprises the steps of:

-   a) enantioselective allylboration of aldehyde (1), to obtain chiral    allylic sec alcohol (3);-   b) esterification of allylic sec alcohol (3) with TBS protected    carboxylic acid (15) with subsequent deprotection to give allylic    alcohol (17); and-   c) ring closing metathesis reaction of compound (17) in presence of    Grubbs II catalyst, gives the desired dacanolides such as    Stagonolide F or Aspinolide A (In stagonolide F the OH group and    methyl are trans)

In accordance with scheme 5, the aldehyde compound (1) undergoesenantioselective allylboration in presence ofallyldiisopinocamphenylborane at temperature in the range of −120° C. to−80° C. for 1-2 hrs in non-polar organic solvents such as, diethylether, pentane, cyclopentane, benzene, toluene, 1,4-dioxane, chloroformor mixtures thereof preferably mixture of diethyl ether-pentane,followed by treatment with NaOH and aqueous H₂O₂ to obtain chiralallylic alcohol (3) in 71% yield with 99% ee.

The carboxylic acid (15) on esterification with allylic alcohol (3) inpresence of EDCl HCl, DMAP in DCM at temperature range 0° to 30° C. for5 to 8 hrs affords 86% yield of compound (16), followed by deprotectionof TBS in presence of TBAF in THF for 6-8 hrs gives allylic alcohol (17)in 82% yield. Further the ring closing metathesis reaction of allylicalcohol (17) in presence of Grubbs II catalyst (5 to 15%) in dry DCM for24 hrs yields 62% of desired decanolides i.e. Aspinolide-A.

In another embodiment, the chiral allylic alcohol (3) can be preparedfrom ethyl acetoacetate (41) as described in scheme 6:

In accordance with scheme 6, Noyori asymmetric hydrogenation of ethylaceoacetate (41) in presence of 0.1% of BINAP-Ru dichloride, NEt3 (0.1mol %), 2N HCl (0.1 mol %), MeOH, H₂ (100 psi) gives chiral hydroxyester (43) in 95% yield with 98% ee. followed by protection of hydroxygroup in presence of TBS-Cl, imidazole in DCM at temperature range 0° C.to 30° C. for 1 to 3 hrs affords TBS protected ester (44) in 97% yield,which on further reduction in presence of DIBAL-H in toluene attemperature ranging from −70° to −80° C. for 0.5 to 2 hrs yields 85% ofaldehyde (45) which on Wittig reaction in presence of n-BuLi, Ph₃P═CH₃Iin dry THF at temperature range −50° to room temperature for 2-4 hrsgives the olefin (46) in 73% yield, the subsequent deprotection of TBSin presence of TBAF in THF at temperature range −5° C. to 0° C. for 1-3hrs affords allylic alcohol (3) in 81% yield.

In another embodiment the TBS protected carboxylic acid (15) can besynthesized by two methods. The first method for the preparation of TBSprotected carboxylic acid (15) is illustrated in scheme 7.

In accordance with scheme 7, the TBS protected carboxylic acid (15) canbe synthesized from 1,5 diol (1c), followed by the similar steps asdescribed hereinabove in scheme 2.

The second method for the preparation of TBS protected carboxylic acid(15) is illustrated in scheme 8.

In accordance with scheme 8, the TBS protected carboxylic acid (15) canbe synthesized from 1,5 diol, followed by the similar steps as describedhereinabove in scheme 3.

In an embodiment, the present invention provides the spectral data forthe intermediate compounds synthesized by the process described above.Accordingly, the IR spectra are recorded on an FT-IR spectrometer. The¹H and ¹³C NMR spectra are recorded on 200/400/500 MHz and 50/100/125MHz NMR spectrometer respectively in CDCl3/CD3OD/DMSO-d6 solvents.

In an embodiment, the compound Decanolides of the instant are used asanti-bacterial, anti-fungal and phytotoxic agents.

The following examples are given by way of illustration of the presentinvention and therefore should not be construed to limit the scope ofthe invention.

EXAMPLES Example 1: Compound of Formula 2c;5-((tert-butyldimethylsilyl)oxy)pentan-1-ol

To a solution of 1,5-pentane diol in dry CH₂Cl₂ at 0° C. was addedimidazole (1.5 equiv.) and tert-butyldimethylsilyl chloride (1.2 equiv).The reaction mixture was stirred at 25° C. for 2 h. After completion ofreaction (monitored by TLC), it was diluted with CH₂Cl₂, washed withwater, brine and dried over anhydrous Na₂SO₄. Removal of solvent underreduced pressure gave the crude product which was further purified bycolumn chromatography to yield 2c as a colorless liquid.

IR (CHCl₃): 760, 835, 1090, 1255, 1463, 2935, 3354 cm⁻¹; ¹H NMR (200MHz, CDCl₃): δ 0.02 (s, 6H), 0.87 (s, 9H), 1.38-1.67 (m, 6H), 1.7 (brs,1H), 3.56-3.64 (m, 4H); ¹³C NMR (50 MHz, CDCl₃): δ −5.2, 18.4, 22.1,26.0, 32.8, 62.8, 63.1.

Example 2: Compound of Formula 3b;5-((tert-butyldimethylsilyl)oxy)pentanal

To a well stirred solution of 2c in dry CH₂Cl₂ at 0° C. were added(diacetoxyiodo)benzene (1.1 equiv) and TEMPO free radical (0.1 equiv).The reaction mixture was warmed to room temperature and stirred for 1 h.The reaction mixture was quenched with saturated solution of sodiumthiosulphate solution, the aqueous mixture was extracted with CH₂Cl₂.The organic layer was washed with saturated NaHCO₃ solution and brineand dried over anhydrous Na₂SO₄. Evaporation of the solvent providedaldehyde 3b a colorless liquid.

IR (CHCl₃): 777, 837, 1047, 1257, 1472, 1720, 2858, 2955 cm⁻¹; ¹H NMR(200 MHz, CDCl₃): δ 0.04 (s, 6H), 0.89 (s, 9H), 1.54-1.75 (m, 4H),2.42-2.50 (m, 2H), 3.58 (t, J=6.1 Hz, 2H); ¹³C NMR (50 MHz, CDCl₃): δ−5.3, 18.3, 18.6, 25.9, 32.11, 43.6, 62.5.

Example 3: Compound of Formula 4b;(S)-5-((tert-butyldimethylsilyl)oxy)pentane-1,2-diol

To a stirred precooled (−20° C.) acetonitrile solution of aldehyde 3band nitrosobenzene (1.0 equiv.) D-proline (20 mol %) was added. Thereaction mixture was allowed to stir at the same temperature for 24 hfollowed by the addition of methanol and NaBH₄ (2.0 equiv.) to thereaction mixture, which was stirred for 10 min After addition ofphosphate buffer, the resulting mixture was extracted with EtOAc and thecombined organic phases were dried over anhydrous. Na₂SO₄ andconcentrated to give the crude aminoxy alcohol which was directly takenup for next step without further purification. To a MeOH solution of thecrude aminoxy alcohol was added 10% Pd/C & stirred under H₂ (1 atm.) at25° C. for 24 h. After completion of reaction (monitored by TLC), it wasfiltered over celite plug (MeOH eluent) and solvent evaporated underreduced pressure to give the corresponding diol as a colourless oil.

IR (CHCl₃): 668, 775, 835, 1006, 1097, 1256, 1463, 1471, 2857, 2929,2954, 3361 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 0.02 (s, 6H), 0.83 (s, 9H),1.37-1.67 (m, 4H), 2.42 (brs, 1H), 3.35-3.86 (m, 6H); ¹³C NMR (50 MHz,CDCl₃): δ −5.35, 18.32, 25.94, 28.98, 30.04, 63.31, 66.63, 71.98.

Example 4: Compound of Formula 5b;(S)-tert-butyldimethyl(3-(oxiran-2-yl)propoxy)silane

A solution of diol 4b in CH₂Cl₂ was treated with tosyl chloride (1.1equiv) and triethylamine (2.0 equiv) at 0° C. After being stirred for 15min, the mixture was extracted with CH₂Cl₂, washed with water & combinedorganic phases were dried over anhyd. Na₂SO₄ and concentrated to givethe crude tosylate, which was purified by column chromatography oversilica gel to give epoxide 5b as a colourless oil.

IR (CHCl₃): 776, 836, 938, 965, 1006, 1101, 1255, 1463, 1471, 2857,2955, 2955 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 0.04 (s, 6H), 0.89 (s, 9H),1.57-1.71 (m, 4H), 2.44-2.48 (dd, J=7.1 Hz, 3H), 2.46 (br.s, 1H),3.60-3.73 (m, 3H), 4.17-4.28 (m, 3H), 6.07 (d, J=15.7 Hz, 1H), 6.82-6.93(m, 1H); ¹³C NMR (50 MHz, CDCl₃): δ −5.29, 18.34, 25.97, 29.05, 46.98,52.06, 62.57.

Example 5: Compound of Formula 6a:(S)-6-((tert-butyldimethylsilyl)oxy)hex-1-en-3-ol

To a stirred solution of trimethylsulfonium iodide (7.98 g, 39.12 mmol)in dry DMSO (90 mL) was added NaH (1.38 g, 60.18 mmol) at 25° C. After30 min, epoxide 5b (6.5 g, 30.09 mmol) in dry DMSO (15 mL) wasintroduced drop-wise and the reaction mixture stirred for 2 h. Aftercompletion of the reaction as monitored by TLC, it was quenched withwater and extracted with diethyl ether (3×100 mL). The combined extractswere washed with brine, dried over anhydrous. Na₂SO₄ and concentratedunder reduced pressure. The crude product was then purified by columnchromatography using petroleum ether/EtOAc (8:2 v/v) to give allylicalcohol (6.0 g) as a colorless liquid.

IR (CHCl₃): 692, 776, 837, 939, 969, 1005, 1104, 1255, 1361, 1388, 1443,1471, 2956, 3354 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 0.02 (s, 6H), 0.84 (s,9H), 1.54-1.60 (m, 4H), 2.61 (br s, 3H), 3.56-3.62 (t, J=6 Hz 2H), 4.06(m, 1H), 4.99-5.23 (m, 2H), 5.71-5.88 (m, 1H); ¹³C NMR (50 MHz, CDCl₃):δ −5.32, 18.38, 26.00, 28.77, 34.42, 63.37, 72.59, 114.30, 141.29.

Example 6: Compound of Formula 7a:(S)-10,10,11,11-tetramethyl-5-vinyl-2,4,9-trioxa-10-siladodecane

To allylic alcohol 6a in CH₂Cl₂ at 0° C. were successively added DIPEA(3.0 equiv), DMAP (120 mg), and MeOCH₂Cl (2.2 equiv). The resultingmixture was stirred for 3 h at r.t. (25° C.) the reaction quenched byadding H₂O (10 ml), and the mixture extracted with CH₂Cl₂. The organicextracts were washed with brine (10 ml), dried (anhy. Na₂SO₄) andconcentrated. The crude was purified by column chromatography.

IR (CHCl₃): 775, 835, 1037, 1097, 1257, 1474, 2857, 2929, 2953, cm⁻¹; ¹HNMR (200 MHz, CDCl₃): δ 0.04 (s, 6H), 0.90 (s, 9H), 1.57-1.66 (m, 4H),3.36 (s, 3H), 3.59-3.65 (t, J=6, Hz 2H), 3.97-4.0 (m, 1H), 4.50-4.53 (d,J=3 Hz, 1H), 4.67-4.70 (d, J=3 Hz, 1H), 5.15-5.24 (m, 2H), 5.57-5.75 (m,1H); ¹³C NMR (50 MHz, CDCl₃): δ −4.59, 19.03, 26.67, 29.32, 32.38,55.99, 63.56, 94.27, 117.86, 139.08.

Example 7: Compound of Formula 8a: (S)-4-(methoxymethoxy)hex-5-en-1-ol

To a compound 7a in dry THF was added dropwise 1 M solution oftetrabutylammonium fluoride (2 equiv.) at 25° C. and stirred at thistemperature for 6 h. After completion of reaction (monitored by TLC) thesolvent was removed under reduced pressure and the residue extractedwith ethyl acetate. The organic layer was washed with water, brine anddried over anhydrous Na₂SO₄. The crude product was subjected to flashcolumn chromatography to afford the primary alcohol 8a as a colourlessliquid.

IR (CHCl₃): 1097, 1643, 1447, 2933, 3415 cm-1; ¹H NMR (200 MHz, CDCl₃):1.58-1.74 (m, 4H), 1.85 (br.s, 1H), 3.37 (s, 3H), 3.66 (t, J=6.04, Hz,2H), 4.01 (q, J=5.28, 12.8 Hz, 2H), 4.51 (d, J=6.79 Hz, 1H), 4.68 (d,J=6.79 Hz, 1H), 5.17 (br.s, 1H), 5.23 (d, J=7.55 Hz, 1H), 5.68 (m, 1H);¹³C NMR (50 MHz, CDCl₃): δ 28.32, 31.61, 55.25, 62.19, 77.05, 93.46,177.22, 137.90.

Example 8: Compound of Formula 12: (S)-4-(methoxymethoxy)hex-5-enoicacid

To a MOM protected primary alcohol (450 mg) in CH₃CN: H₂O (4:1) wereadded (diacetoxyiodo)benzene (1.2 g) and TEMPO free radical (86.3 mg) at25° C. and stirred at this temperature for 4 h. After completion ofreaction (monitored by TLC) the solvent was removed under reducedpressure and the residue extracted with ethyl acetate. The organic layerwas washed with water, brine and dried over anhydrous Na₂SO₄. The crudeproduct was subjected to flash column chromatography to afford the acid12 as a colourless liquid. Yield 86%.

IR (CHCl₃): 920, 1029, 1096, 1149, 1255, 1424, 1255, 1149, 1255, 1424,1711, 2888, 2937, 3447 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): 1.86 (q, J=6.79,13.59 Hz, 2H), 2.46 (t, J=6.79 Hz, 2H), 3.36 (s, 3H), 4.02 (q, J=6.79,13.59 Hz, 2H), 4.49 (d, J=6.79 Hz, 1H), 4.65 (d, J=6.79 Hz 1H), 5.19 (d,J=7.55 Hz, 1H), 5.24 (d, J=7.55 Hz, 1H), 5.66 (m, 1H); ¹³C NMR (50 MHz,CDCl₃): δ 29.42, 30.1, 54.89, 75.7393.12, 117.32, 136.90, 178.71.

Example 9: (R)-Ethyl (−)-3-hydroxybutyrate, (43)

Ethyl acetoacetate (7.5 g) and dry methanol (25 mL) were mixed anddeoxygenated with flowing nitrogen for five minutes. The catalyst[(R)—Ru(BINAP)Cl₂]₂.NEt3 (0.1 mol %) was added along with 2N HCl (0.1mol %). The mixture was transferred to a standard Parr reactor apparatusand flushed by evacuating and refilling with hydrogen several times. Theapparatus was heated at 50° C. with stirring under 100 psi of hydrogenfor 16 h. After completion of reaction (monitored by TLC) the reactionwas cooled and concentrated under reduced pressure. The residue wassubjected to column chromatographic purification with petroleumether/ethyl acetate (9:1 v/v) to get pure (R)-alcohol 43 as a colorlessliquid.

[α]_(D) ²⁵ −46.0 (c 1.0, CHCl₃); [α]_(D) ²⁵ −46.0 (c 1.0, CHCl₃); 98% ee(Mosher ester); IR (CHCl₃, cm⁻¹) 3441.7, 2978.6, 2935.7, 1734.0, 1636.1,1458.1; ¹H NMR (200 MHz, CDCl₃): δ 4.12-4.22 (m, 3H), 3.20 (d, J=3.8 Hz,1H), 2.42-2.45 (m, 2H), 1.21-1.31 (m, 6H); ¹³C NMR (50 MHz, CDCl₃): δ172.5, 64.2, 60.5, 43.2, 22.6, 14.1. Analysis: C₆H₁₂O₃ requires C,54.53; H, 9.15. found C, 54.56; H, 9.35%.

Example 10: (R)-(−)-Ethyl (tert-butyldimethyl silyloxy)butyrate, (44)

To a solution of ethyl (R)-(−)-3-hydroxybutyrate 43 in dry CH₂Cl₂ at 0°C. was added imidazole (1.5 equiv) and tert-butyldimethylsilyl chloride(1.2 equiv.). The reaction mixture was stirred at 25° C. for 2 h. Aftercompletion of reaction (monitored by TLC), it was diluted with CH₂Cl₂,washed with water, brine and dried over anhydrous Na₂SO₄, Concentrationand purification by column chromatography with petroleum ether/ethylacetate (49:1 v/v) gave aldehyde 44 as a colorless liquid.

[α]_(D) ²⁵ −26.0 (c 1.0, CH₂Cl₂); lit.¹² [α]_(D) ²⁵ −25.5 (c 1.0,CH₂Cl₂); IR (CHCl₃ cm⁻¹) 2958, 2931, 2897, 2857, 1739, 1473, 1447; ¹HNMR (200 MHz, CDCl₃): δ 4.19-4.28 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 2.44(dd, J=7.4, 14.5 Hz, 1H), 2.32 (dd, J=5.4, 14.5 Hz, 1H), 1.22 (t, J=7.2Hz, 3H), 1.17 (d, J=6.1 Hz, 3H), 0.82 (s, 9H), δ 0.05 (s, 3H), δ 0.04(s, 3H); ¹³C NMR (50 MHz, CDCl₃): δ171.2, 65.8, 59.9, 44.8, 25.7, 23.9,17.9, 14.2, −4.5, −5.0. Analysis: C₁₂H₂₆O₃Si requires C, 58.49; H, 10.63found C, 58.54; H, 10.56%.

Example 11: (R)-(−)-Ethyl (tert-butyldimethylsilyloxy)butanal, (45)

To a stirred solution of ester 44 in dry toluene (250 mL), a solution ofdiisobutylaluminium hydride (1.0 equiv.), 1M in cyclohexane was addeddropwise at −78° C. and stirred at said temperature for 1 h. Aftercompletion of reaction (monitored by TLC), it was diluted with asaturated solution of Rochelle salt (1 g) and stirred for further 3 h.The organic phase was separated and the aqueous phase extracted twicewith CH₂Cl₂. The combined organic phase was washed with water, brine anddried over anhydrous Na₂SO₄. Removal of solvent under reduced pressureand column chromatographic purification with petroleum ether/ethylacetate (19:1 v/v) gave aldehyde 45 as a colorless liquid.

[α]_(D) ²⁵ −13.6 (c 1.6, CH₂Cl₂); lit.¹² [α]_(D) ²⁵ −11.3 (c 1.0,CH₂Cl₂); IR (CHCl₃, cm⁻¹) 2957, 2930, 2896, 2858, 1729, 1473, 1463,1377, 1362; ¹H NMR (200 MHz, CDCl₃): δ 9.76 (dd, J=2.1, 2.7 Hz, 1H),4.25-4.40 (m, 1H), 2.40-2.59 (m, 2H), 1.19 (d, J=6.2 Hz, 3H), 0.84 (s,9H), 0.08 (s, 3H), 0.06 (s, 3H); ¹³C NMR (50 MHz, CDCl₃): δ 202.0, 64.5,52.9, 25.7, 24.1, 17.9, −4.4, −5.0. Analysis: C₁₀H₂₂O₂Si requires C,59.35; H, 10.96. found C, 59.38; H, 10.97%.

Example 12: (R,E)-Ethyl 5-(tert-butyldimethylsilyloxy)hex-2-enoate (5)

To a solution of aldehyde 4 in dry THF (200 mL) at 25° C. was addedPh₃P=CHCOOEt (2.0 equiv.) and the reaction mixture was stirred for 12 h.After completion of reaction (monitored by TLC), solvent was distilledoff under reduced pressure and the crude mass on flash chromatographicpurification gave the α,β-unsaturated ester 5 as a colourless liquid.

IR (CHCl₃, cm⁻¹) 775, 836, 1003, 1045, 1093, 1132, 1175, 1222, 1258,1317, 1723; ¹H NMR (200 MHz, CDCl₃): δ 0.04 (s, 6H), 0.88 (s, 9H), 1.14(d, J=6.61 Hz 3H), 1.25 (t, J=6.61 Hz, 3H), 2.23-2.31 (m, 2H), 3.80-3.95(m, 1H), 4.09-4.19 (q, J=7.03, 14.06 Hz 2H), 5.73-5.80 (d, J=15.81 Hz,1H), 6.81-6.97 (m, 1H); ¹³C NMR (50 MHz, CDCl₃): δ −4.18, −4.50, 14.30,18.09, 23.83, 25.83, 42.46, 60.00, 67.64, 123.25, 145.85, 166.17.

Example 13: (R,E)-Ethyl 5-(tert-butyldimethylsilyloxy)hex-2-enoate 6

To a stirred solution of ester 5 in dry toluene (250 mL), a solution ofdiisobutylaluminium hydride (2.0 equiv., 1M in cyclohexane) was addeddropwise at −78° C. and stirred at this temperature for 1 h. Aftercompletion of reaction (monitored by TLC), it was diluted with asaturated solution of Rochelle salt and stirred for further 3 h. Theorganic phase was separated and the aqueous phase extracted twice withCH₂Cl₂. The combined organic phase was washed with water, brine anddried over anhydrous Na₂SO₄. Removal of solvent under reduced pressureand flash chromatographic purification gave 6 as a colorless liquid.

IR (CHCl₃, cm⁻¹) 690, 775, 840, 940, 972, 1010, 1103, 1253, 1361, 1387,1442, 1468, 2950, 3348; ¹H NMR (200 MHz, CDCl₃): δ 0.04 (s, 6H), 0.90(s, 9H), 1.11 (d, J=6.86 Hz 3H), 2.11-2.23 (m, 2H), 3.61-3.86 (m, 1H),4.02-4.11 (m, 2H), 5.60-5.65 (m, 2H); ¹³C NMR (50 MHz, CDCl₃): δ −3.95,−4.58, 18.33, 26.25, 42.90, 60.76, 64.06, 68.75, 129.97, 131.65.

Example 14: (R,E)-Ethyl 5-(tert-butyldimethylsilyloxy)hex-2-enoate (7)

The catalyst(R)-α,α-Bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanoltri-methylsilyl ether (1.2 g, 10 mol %) was added at ambient temperatureto a solution of aldehyde (4.5 g, 19.73 mmol) in CH₂Cl₂ (60 mL) followedby the addition of 35% H₂O₂ (aq.) (1.3 equiv.). After the completion ofreaction (monitored by TLC), it was diluted with MeOH (60 mL) and cooledto 0° C. followed by addition of NaBH₄ (1.49 g, 39.47 mmol). The mixturewas then stirred for 10 min, quenched with sat. NH₄Cl and extracted withCH₂Cl₂. The organic layer was separated, dried over anhydrous Na₂SO₄ andthe solvent removed under reduced pressure. The crude product waspurified by column chromatography with petroleum ether/EtOAc (8:2 v/v)to give epoxy alcohol (2.57 g) as a colourless liquid.

IR (CHCl₃, cm⁻¹) 775, 836, 1006, 1050, 1072, 1130, 1256, 2857, 2929,2956, 3437; ¹H NMR (200 MHz, CDCl₃): δ 0.08 (s, 6H), 0.89 (s, 9H), 1.16(d, J=6.86 Hz 3H), 1.44-1.56 (m, 1H), 1.67-1.81 (m, 2H), 2.89-2.93 (m,1H), 3.02-3.09 (m, 1H), 3.54-3.66 (m, 1H), 3.88-4.07 (m, 2H); ¹³C NMR(50 MHz, CDCl₃): δ −4.87, −4.45, 18.02, 24.32, 25.82, 41.82, 53.39,58.82, 61.50, 66.23.

Example 15: (R,E)-Ethyl 5-(tert-butyldimethylsilyloxy)hex-2-enoate (9)

To a stirred solution of epoxy alcohol (2.5 g, 10.14 mmol) in dryether-acetonitrile mixture (3:1, 40 ml) at 0° C. under nitrogenatmosphere were added imidazole (1.03 g, 15.21 mmol), triphenylphosphine(3.98 g, 15.21 mmol) and iodine (4.61 g, 18.25 mmol) successively. Theresulting reaction mixture was stirred for 1 h at the same temperatureand then diluted with cold ether (20 mL), and filtered through asintered funnel. The residue was washed with ether (3×50 mL), dried overanhydrous Na₂SO₄ and concentrated in vacuo. Purification of the cruderesidue by column chromatography (9:1 v/v) gave the pure product epoxyiodide (3.5 g) as a pale yellow liquid.

A mixture of the above epoxy iodide (3.47 g, 9.74 mmol), NaI (3.62 g,24.36 mmol) and freshly activated zinc (0.126 g, 1.94 mmol) in dry MeOH(45 ml) was refluxed for 6 h under nitrogen atmosphere. The solution wasfiltered and the residue washed with MeOH (2×25 mL). The combinedfiltrates were concentrated and the residue was taken in ethyl acetate(50 mL), washed with water (2×25 mL), brine (3×50 mL), dried overanhydrous Na₂SO₄ and concentrated undered reduced pressure. The crudecompound was purified by column chromatography using petroleumether/EtOAc (8:2 v/v) to afford the allyl alcohol (2.0 g) as a colorlessoil.

IR (CHCl₃, cm⁻¹) 775, 836, 1040, 1078, 1128, 1255, 2856, 2929, 2957,3441; ¹H NMR (200 MHz, CDCl₃): δ 0.09 (s, 6H), 0.90 (s, 9H), 1.22 (d,J=6.67 Hz 3H), 1.59-1.67 (m, 2H), 3.21 (br.s, 1H), 4.15-4.27 (m, 1H),4.38-4.46 (m, 1H), 5.04-5.29 (m, 2H), 5.77-5.93 (m, 1H); ¹³C NMR (50MHz, CDCl₃): δ −4.89, −4.31, 18.01, 23.19, 25.89, 44.57, 67.10, 69.95,113.84, 141.22.

Example 16: (R,E)-Ethyl 5-(tert-butyldimethylsilyloxy)hex-2-enoate (10)

MOM protection procedure same as above. (example no. 6)

¹H NMR (200 MHz, CDCl₃): δ 0.06 (s, 6H), 0.89 (s, 9H), 1.44 (d, J=6.99Hz 3H), 1.59-1.67 (m, 2H), 3.37 (s, 3H), 3.89-4.14 (m, 2H), 4.52-4.69(dd, J=6.92, 29.08 Hz 2H), 5.13-5.22 (m, 2H), 5.61-5.81 (m, 1H); ¹³C NMR(50 MHz, CDCl₃): δ −4.89, −4.31, 18.01, 23.19, 25.89, 44.57, 67.10,69.95, 113.84, 141.22.

Example 17: (2R,4S)-4-(methoxymethoxy)hex-5-en-2-ol (11)

TBS deprotection procedure same as above (example no. 7) [α]_(D) ²⁵−108.6 (c 1.6, CH₂Cl₂); lit.¹² [α]_(D) ²⁵ −109.2 (c 1.50, CHCl₃); IR(CHCl₃, cm⁻¹) 1037, 1099, 1153, 1597, 2925, 3433; ¹H NMR (200 MHz,CDCl₃): δ 1.18 (d, J=6.20 Hz 3H), 1.63-1.72 (m, 2H), 2.56 (br.s, 1H),3.40 (s, 1H), 3.97-4.16 (m, 1H), 4.25-4.34 (m, 1H), 4.53 (d, J=6.60 Hz1H), 4.66 (d J=6.77 Hz, 1H), 5.16-5.27 (m, 2H), 5.56-5.83 (m, 1H); ¹³CNMR (50 MHz, CDCl₃): δ23.68, 44.23, 56.00, 64.51, 75.63, 94.59, 117.10,138.06.

Example 18: (4S)-(2R,4S)-4-(methoxymethoxy)hex-5-en-2-yl4-(methoxymethoxy)hex-5-enoate (13)

Esterification of MOM protected allylic alcohol (11) (0.5 g) withcarboxylic acid compound (12) (0.6 g) was done carried by using EDCI.HCl(0.891 g) & catalytic DMAP (30 mg) in CH₂Cl₂ at 0-25° C. to obtain estercompound (13).

[α]_(D) ²⁵ −125.6 (c 1.6, CH₂Cl₂); lit.¹² [α]_(D) ²⁵ −127.6 (c 0.60,CHCl₃); IR (CHCl₃, cm⁻¹) 920, 993, 1030, 1096, 1150, 1732, 2930; ¹H NMR(200 MHz, CDCl₃): δ 1.24 (d, J=6.39 Hz, 3H), 1.69-1.77 (m, 2H),1.84-1.94 (m, 2H), 2.37-2.41 (m, 2H), 3.32 (s, 1H), 3.37 (s, 1H), 4.02(m 2H), 4.46 (d, J=6.77 Hz, 1H), 4.51 (d, J=6.77 Hz, 1H), 4.66-4.69 (m,2H), 5.06-5.14 (m, 1H), 5.18-5.25 (m, 4H), 5.62-5.71 (m, 2H); ¹³C NMR(50 MHz, CDCl₃): δ20.64, 30.40, 30.45, 42.09, 55.47, 55.69, 67.64,73.66, 77.27, 93.69, 117.38, 117.81, 137.67, 137.98, 172.70.

Example 19:(6E,5S,8S,10R)-4,5,9,10-tetrahydro-5,8-bis(methoxymethoxy)-10-methyl-3H-oxecin-2(8H)-one(14)

A solution of Grubbs 2nd-generation catalyst (10 mol %) in CH₂Cl₂ wasadded dropwise to a solution of diene (13),(2R,4S)-4-(methoxymethoxy)hex-5-en-2-yl(S)-4-(methoxymethoxy)hex-5-enoate) in CH₂Cl₂. The mixture was stirredunder reflux at 45° C. for 24 h. The solvent was evaporated and thecrude product purified by column chromatography.

[α]_(D) ²⁵ −40.6 (c 1.6, CH₂Cl₂); lit.¹² [α]_(D) ²⁵ −42.8 (c 1.21,CHCl₃); IR (CHCl₃, cm⁻¹) 755, 803, 1030, 1098, 1260, 1375, 1450, 1728,1855, 1953, 2851, 1945, 2860, 2930; ¹H NMR (200 MHz, CDCl₃): δ 1.23 (d,J=6.84 Hz, 3H), 1.76-1.88 (m, 2H), 1.97-2.12 (m, 3H), 2.27-2.32 (m, 1H),3.32 (s, 1H), 3.37 (s, 1H), 4.48 (m 2H), 4.48 (d, J=6.80 Hz, 1H), 4.51(d, J=6.77 Hz, 1H), 4.66-4.69 (m, 2H), 5.06-5.14 (m, 1H), 5.18-5.25 (m,4H), 5.62-5.71 (m, 2H); ¹³C NMR (50 MHz, CDCl₃): δ20.64, 30.40, 30.45,42.09, 55.47, 55.69, 67.64, 73.66, 77.27, 93.69, 117.38, 117.81, 137.67,137.98, 172.70.

Example 20: Compound of Formula (30) ethyl(4R,7R,E)-7-((tert-butyldimethylsilyl)oxy)-4-hydroxyoct-2-enoate

To a precooled (−20° C.) R.B. flask, solution of aldehyde(R)-5-((tert-butyldimethylsilyl)oxy)hexanal in CH₃CN, nitrosobenzene (1equiv) solvent and L-proline (20 mol %) were added. The reaction mixturewas stirred for 24 h at −20° C. Triethylphosphonoacetate (1.8 equiv),LiCl (1.1 equiv), DBU (1.5 equiv) were added to the above mixture at 0°C. and stirred for 2 h. On completion of reaction (by checking TLC), thesolvent CH₃CN was evaporated, the organic layer was extracted with EtOAcand dried over anhydrous Na₂SO₄. The solvent was removed in vacuum andconcentrated. To the crude Cu(OAc)₂ (30 mol %) was added in EtOH andstirred for 24 h. After the completion of reaction (monitored by TLC),EtOH was removed in vacuum and the crude was subjected tochromatographic separation. The eluent was allowed to come out in asolution of pet ether:EtOAc=80:20 as pale yellow oily liquid,[α]²⁵=+11.6 (c 1.5, CHCl3), IR (KBr): mmax 3442, 2927, 2855, 1721, 1656,1465, 1255, 1043, 774 cm1; 1H NMR (CDCl3, 200 MHz): δ 6.89 (dd, J=15.8Hz, 1H), 6.02 (dd, J=15.8 Hz, 1H), 4.28-4.20 (m, 1H), 4.18 (q, J=14.3,6.8 Hz, 2H), 3.94-3.87 (m, 1H), 1.74-1.52 (m, 4H), 1.30 (t, J=6.8 Hz,3H), 1.16 (d, J=6.8 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3,50 MHz): d 166.3, 150.2, 120.0, 71.0, 68.4, 60.1, 35.3, 32.2, 25.9,23.1, 18.1, 14.3, −4.3, −4.6.

Example 21: Compound of Formula (32)(4R,7R,E)-7-((tert-butyldimethylsilyl)oxy)-4-(methoxymethoxy)oct-2-enal

To a stirred solution of α,β-unsaturated ester (31, ethyl(4R,7R,E)-7-((tert-butyldimethylsilyl)oxy)-4-(methoxymethoxy)oct-2-enoate)dissolved in dry THF at −78° C., DIBAL-H (1 equiv) was added and stirredfor 1 h. On completion of the reaction (by checking TLC), the mixturewas quenched with dilute solution of potassium hydrogen tartarate (1 g,10% aq. Sol.). The organic layer was extracted in DCM, washed withbrine, dried over anhydrous Na₂SO₄. The solvent was removed in vacuum,concentrated and subjected for chromatographic separation. The eluentwas allowed to come in a solution of pet ether:EtOAC=95:5 as a colorlessliquid. [α]²⁵=+22.5 (c=1.55, CHCl3); 1H NMR (200 MHz, CDCl₃): 0.05 (d,6H, J=2.0 Hz), 0.90 (s, 9H), 1.14 (d, 3H, J=6.0 Hz), 1.35-1.83 (m, 4H),3.36 (s, 3H), 3.74-3.84 (m, 1H), 4.24-4.35 (m, 1H), 4.6 (m, 2H),6.16-6.28 (dd, 1H, J=7.1, 7.7 Hz), 6.60-6.71 (dd, 1H, J=6.0, 5.8 Hz),9.8 (d, 1H, J=7.7 Hz); 13C NMR (50 MHz, CDCl3): −4.8, −4.4, 23.8, 25.8,30.8, 34.8, 55.7, 68.2, 75.5, 95.0, 132.0, 156.7, 193.3.

Example 22: Compound of Formula (33) ethyl(2Z,4E,6R,9R)-9-((tert-butyldimethylsilyl)oxy)-6-(methoxymethoxy)deca-2,4-dienoate

In a solution of dry THF, NaH (1.5 equiv) and Ethyl P,P-bis(2,2,2 trifluoro ethyl) phos-phonoacetate (1.8 equiv) at −78° C. were added andstirred for 1 h. This was followed by dropwise addition ofα,β-unsaturated aldehyde (32), dissolved in dry THF using a syringe tothe above mixture and the reaction was stirred for another 1 h. Aftercompletion of the reaction (monitored by TLC), the mixture was quenchedwith ice and the organic layer was extracted using ether and washed withbrine and dried over anhydrous Na₂SO₄. The solvent was removed invacuum, concentrated and the crude was purified by chromatographictechnique (EtOAc:pet ether=10:90). [α]²⁵=+49 (c 1.2, CHCl₃); 1H NMR(CDCl3, 200 MHz): 7.46 (m, 1H), 6.55 (t, 1H), 5.88 (q, 1H), 5.69 (d,1H), 4.53-4.68 (m, 2H), 4.18 (m, 3H), 3.80 (m, 1H), 3.36 (s, 3H),1.54-1.62 (m, 4H), 1.30 (m, 4H), 1.11 (d, 3H), 0.88 (s, 9H), 0.04 (s,6H).

Example 23: Compound of Formula (34) ethyl(2Z,4E,6R,9R)-9-(oxy)-6-(methoxymethoxy)deca-2,4-dienoate

To a stirred solution of TBS protected alcohol (33,(4R,7R,E)-7-((tert-butyldimethylsilyl)oxy)-4-(methoxymethoxy)oct-2-enal)in THF, TBAF (2 equiv) was added and stirred for 2 h. After completionof the reaction (monitored by TLC), the organic layer was extractedusing ether and washed with brine and dried over dried over anhydrousNa₂SO₄. The solvent was removed in vacuum, concentrated and the crudewas purified by chromatographic technique (EtOAc:pet ether=20:80).[α]25=+68 (c 0.44, CHCl3), 1H NMR (CDCl3, 200 MHz): 7.48 (m, 1H),6.25-6.61 (m, 1H), 5.64-6.02 (m, 2H), 4.67 (m, 2H), 4.20 (m, 3H), 3.80(m, 1H), 3.36 (s, 3H), 1.90 (br s, 1H), 1.54-1.71 (m, 4H), 1.30 (t, 3H),1.18 (d, 3H).

Example 24: Compound of Formula (36)(3Z,5E,7R,10R)-7-(methoxymethoxy)-10-methyl-7,8,9,10-tetrahydro-2H-oxecin-2-one

To a stirred solution of acid (35((2Z,4E,6R,9R)-9-(oxy)-6-(methoxymethoxy)deca-2,4-diene acid) in dryTHF, 2,4,6-trichlorobenzoylchloride (1.5 equiv), Et₃N (1.5 equiv) wereadded at 0° C. and stirred for 2 h. The reaction mixture was added to asolution of DMAP (4.5 equiv) in dry toluene at 80° C. for 24 h. Oncompletion of reaction (by checking TLC), it was cooled to roomtemperature (25° C.), the solvent was evaporated, the organic layer wasextracted with EtOAc and dried over anhydrous Na₂SO₄. The solvent wasremoved in vacuum and concentrated. The crude was purified bychromatographic technique (EtOAc:pet ether=10:90). [α]²⁵=+47.4 (c=0.8,CHCl3); 1H NMR (300 MHz, CDCl3): 1.22 (d, 3H, J=6.2 Hz), 1.57-1.94 (m,4H), 3.35 (s, 3H), 4.15 (td, 1H, J=4.0, 9.0 Hz), 4.53 (d, 1H, J=6.8 Hz),4.70 (d, 1H, J=6.6 Hz), 5.00 (m, 1H), 5.64 (dd, 1H, J=9.6, 15.4 Hz),5.85 (d, 1H, J=10.5 Hz), 6.16 (d, 1H, J=15.1 Hz), 6.62 (d, 1H, J=10.3Hz); 13C NMR (75 MHz, CDCl₃): 21.4, 29.7, 39.0, 55.5, 73.1, 73.2, 95.0,124.1, 128.1, 138.5, 140.6, 168.0.

Example 25: Stagonolide-E(3Z,5E,7R,10R)-7-hydroxy-10-methyl-7,8,9,10-tetrahydro-2H-oxecin-2-one

To a stirred solution of the macrolactone 36 (20 mg) in THF, 2N HCl 1 mlsolution was added and stirred for 2 h at 25° C. After completion of thereaction (monitored by TLC), the organic layer was extracted using etherand washed with brine and dried over dried over anhydrous Na₂SO₄. Thesolvent was removed in vacuum and concentrated. The crude was purifiedby chromatographic technique (EtOAc:pet ether=20:80). Yield: 78%

[α]²⁵=−180.2 (C=0.3, CHCl₃). 1H NMR (CDCl₃, 200 MHz) δ 6.62 (d, J=11.6Hz, 1H), 6.12 (br, J=15.4 Hz, 1H), 5.85 (d, J=11.6 Hz, 1H), 5.74 (dd,J=15.3, 9.4 Hz, 1H), 4.98 (m, 1H), 4.25 (m, 1H), 1.94-1.6 (m, 4H), 1.22(d, J=6.8 Hz, 3H); 13C NMR (CDCl3, 50 MHz): δ 168.1, 140.2, 139.4,126.5, 125.6, 73.5, 73.2, 37.4, 30.3, 21.3.

Example 26: Compound of Formula (22) 6-(benzyloxy)hexan-1-ol

To a stirred solution of 1,6-hexan-diol in dry THF at 0° C., NaH (1.1equiv) was added. After stirring for 30 min, BnBr (1 equiv) was addedslowly dropwise using a syringe and stirred for additional 3 h. Aftercompletion of the reaction (monitored by TLC), it was quenched with iceand the organic layer was extracted using ether and washed with brineand dried over anhydrous Na₂SO₄. The solvent was removed in vacuum andconcentrated. The crude was purified by chromatographic technique(EtOAc:pet ether=20:80). 1H NMR (CDCl₃, 200 MHz) δ 7.3-7.4 (5H, m), 4.5(s, 2H), 3.6 (t, 2H), 3.4 (t, 2H), 1.8 (br s, 1H), 1.6 (m, 4H), 1.4 (m,4H); 13C NMR (CDCl3, 50 MHz): 138.56, 128.34, 127.62, 127.50, 72.87,70.29, 62.63, 32.67, 29.73, 26.03, 25.62.

Example 27: Compound of Formula (23) 6-(benzyloxy)hexanal

To a solution of alcohol (22, 6-(benzyloxy)hexan-1-ol) dissolved in dryDCM, Tempo free radical (0.1 equiv), iodobenzenediacetate (1.1 equiv)were added and stirred at 25° C. On completion of the reaction (bychecking TLC), it was quenched with dilute solution of Na₂S₂O₃. Theorganic layer was extracted in DCM, washed with brine, dried overanhydrous Na₂SO₄. The solvent was removed in vacuum concentrated andsubjected for chromatographic separation. The eluent was allowed to comein a solution of pet ether:EtOAC=95:5 as a colorless liquid. 1H NMR(CDCl₃, 200 MHz): δ 9.8 (s, 1H), 7.2-7.4 (m, 5H), 4.5 (s, 2H), 3.5 (t,2H), 2.4 (t, 2H), 1.6 (m, 4H), 1.4 (m, 4H); 13C NMR (CDCl3, 50 MHz): δ202.75, 138.50, 128.40, 127.68, 127.50, 72.95, 70.03, 43.86, 29.53,25.85, 21.91.

Example 28: Compound of Formula (24) (S)-6-(benzyloxy)hexane-1,2-diol

To a precooled solution of aldehyde (23, 6-(benzyloxy)hexanal) in CH₃CNat −20° C., nitrosobenzene (1 equiv) and D-proline (20 mol %) wereadded, stirred for 24 h. This was followed by addition of NaBH₄ (2equiv) and MeOH to the reaction mixture at 0° C. for 30 min. Oncompletion of the reaction, solvent was evaporated and concentrated. Tothe crude 30 mol % CuSO4 was added in EtOH and stirred for 24 h. Afterthe completion of reaction (monitored by TLC), EtOH was removed invacuum and the crude was subjected to chromatographic separation. Theeluent was allowed to come out in a solution of pet ether:EtOAc=60:40.1H NMR (CDCl₃, 200 MHz): 7.2-7.4 (m, 5H), 4.5 (s, 2H), 3.6 (m), 2H), 3.4(m, 3H), 2.6 (br s, 2H), 1.5 (m, 6H); 13C NMR (CDCl3, 50 MHz): 138.37,128.39, 127.69, 127.50, 72.92, 71.64, 70.22, 66.12, 33.60, 29.64, 22.42.

Example 29: Compound of Formula (25) (S)-2-(4-(benzyloxy)butyl)oxirane

To a stirred solution of diol (24, (S)-6-(benzyloxy)hexane-1,2-diol 24)in CH₂Cl₂ solvent, TsCl (1.1 equiv), Bu₂SnO, DMAP (10 mol %), Et₃N (2equiv) were added and stirred for 2 h. On completion of the reaction (bychecking TLC), the organic layer was extracted in DCM, washed withbrine, dried over anhydrous Na₂SO₄. The solvent was removed in vacuum,concentrated and subjected for chromatographic separation. The eluentwas allowed to come in a solution of pet ether:EtOAC=95:5 ([α]²⁵=5.25 (c2.0, CHCl₃) 1H NMR (CDCl₃, 200 MHz): 7.2-7.4 (m, 5H), 4.5 (s, 2H), 3.46(t, 2H), 2.86-2.88 (m, 1H), 2.69 (dd, J=4.0, 5.1 Hz, 1H), 2.43 (dd,J=2.8, 5.2 Hz, 1H), 1.51-1.66 (m, 6H); 13C NMR (CDCl3, 50 MHz): 138.37,128.39, 127.69, 127.50, 72.92, 70.12, 52.1, 33.30, 29.64, 22.8.

Example 30: Compound of Formula (26) (R)-6-(benzyloxy)hexan-2-ol

To a suspension of LiAlH₄ (1.1 equiv) in dry THF, a solution of epoxide(25, (S)-2-(4-(benzyloxy)butyl)oxirane) in THF was added dropwise at 0°C. The reaction mixture was stirred at this temperature for 30 min Aftercompletion of reaction (monitored by TLC), it was quenched with aq 20%solution of sodium hydroxide (2 mL) at 0° C. The reaction mixture wasfiltered through sintered funnel, dried over anhydrous Na₂SO₄ andconcentrated. Purification by column chromatography with petroleumether/ethyl acetate (90:10) gave the secondary alcohol as a colorlessliquid. [α]²⁵=−7.9 (c 2.0, CHCl3); IR (neat, cm⁻¹): 3354, 2935, 1657,1460, 1416, 1375, 1300; 1H NMR (200 MHz, CDCl3): δ 7.29-7.33 (m, 5H),4.48 (s, 2H), 3.70-3.79 (m, 1H), 3.46 (t, J=6.2 Hz, 2H), 2.0 (br s, 1H),1.41-1.70 (m, 6H), 1.15 (d, J=6.2 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ138.5, 128.3, 127.6, 127.5, 72.9, 70.3, 67.6, 39.0, 29.7, 23.5, 22.4.

Example 31: Compound of Formula (27)(R)-((6-(benzyloxy)hexan-2-yl)oxy)(tert-butyl)dimethylsilane

To a solution of alcohol (26, (R)-6-(benzyloxy)hexan-2-ol) in dry CH₂Cl₂at 0° C. were added imidazole (1.5 equiv) and tert-butyl dimethylsilylchloride (1.2 equiv). The reaction mixture was stirred at 25° C. for 2h. After completion of reaction (monitored by TLC), it was diluted withCH₂Cl₂, washed with water, brine, and dried over anhydrous Na₂SO₄.Removal of the solvent under reduced pressure gave the crude productwhich was purified by column chromatography with pure petroleum ether tothe product as a colorless liquid [α]²⁵=−10.0 (c 1.0, CHCl3); IR (neat,cm_1): 2929, 2856, 1471, 1462, 1455, 1373, 1361; 1H NMR (200 MHz,CDCl3): δ 7.31-7.33 (m, 5H), 4.48 (s, 2H), 3.72-3.81 (m, 1H), 3.45 (t,J=6.4 Hz, 2H), 1.33-1.63 (m, 6H), 1.12 (d, J=6.1 Hz, 3H), 0.88 (s, 9H),0.04 (s, 6H); 13C NMR (50 MHz, CDCl3): δ 138.7, 128.2, 127.5, 127.3,72.8, 70.3, 68.4, 39.5, 29.8, 25.9, 23.8, 22.4, 18.1, −4.4, −4.7.

Example 32: Compound of Formula (28)(R)-5-((tert-butyldimethylsilyl)oxy)hexan-1-ol

A mixture of benzyl ether, (27,(R)-((6-(benzyloxy)hexan-2-yl)oxy)(tert-butyl)dimethylsilane), 10% Pd/C,and catalytic amount of triethylamine (2 drops) was stirred under H₂ (1atm) at 25° C. After completion of reaction (monitored by TLC), it wasfiltered through Celite (MeOH eluent) and the solvent evaporated underreduced pressure to afford the title compound as a slightly yellowcolored oil. [α]²⁵=−13:8 (c 1.6, CHCl3); IR (neat, cm_1): 3438.4,2930.4, 2857.9, 1225.6, 1099.5, 1050.13; 1H NMR (200 MHz, CDCl3): d3.70-3.78 (m, 1H), 3.59 (t, J=6.3, 2H), 1.62 (br s, 1H), 1.32-1.55 (m,6H), 1.09 (d, J=6.1 Hz, 3H), 0.84 (s, 9H), 0.04 (s, 6H); 13C NMR (50MHz, CDCl3): d 68.5, 62.6, 39.4, 32.7, 25.9, 23.7, 21.7, 18.1, −4.41,−4.71.

Example 33: Compound of Formula (29)(R)-5-((tert-butyldimethylsilyl)oxy)hexanal

To a solution of alcohol (28,(R)-5-((tert-butyldimethylsilyl)oxy)hexan-1-ol) dissolved in dry DCM,Tempo free radical (0.1 equiv), iodobenzenediacetate (1.1 equiv) wereadded and stirred at 25° C. On completion of the reaction (by checkingTLC), it was quenched with dilute solution of Na₂S₂O₃. The organic layerwas extracted in DCM, washed with brine, dried over anhydrous Na₂SO₄.The solvent was removed in vacuum, concentrated and subjected forchromatographic separation. The eluent was allowed to come in a solutionof pet ether:EtOAC=95:5 as a colorless liquid. [α]²⁵=−12:0 (c 3.0,CHCl3); IR (neat, cm-1): 3020, 2930, 2857, 1722, 1572, 1472, 1215; 1HNMR (200 MHz, CDCl3): δ 9.71 (t, J=1.8 Hz, 1H), 3.71-3.83 (m, 1H),2.33-2.39 (dt, J=7.1, 8.8 Hz, 2H), 1.54-1.70 (m, 2H), 1.35-1.43 (m, 2H),1.09 (d, J=6.0 Hz, 3H), 0.84 (s, 9H), 0.05 (s, 6H); 13C NMR (50 MHz,CDCl3): δ 202.0, 67.6, 43.4, 38.46, 25.40, 23.26, 17.85, 17.59, −4.84,−5.23.

Example 34: Compound of Formula (31) ethyl(4R,7R,E)-7-((tert-butyldimethylsilyl)oxy)-4-(methoxymethoxy)oct-2-enoate

To a stirred solution of the compound (30, ethyl(4R,7R,E)-7-((tert-butyldimethylsilyl)oxy)-4-hydroxyoct-2-enoate) in dryCH₂Cl₂ solvent, MOMCl (2 equiv), DIPEA (3 equiv) were added and stirredfor 8 h. On completion of the reaction (by checking TLC), the organiclayer was extracted in DCM, washed with brine, dried over anhydrousNa₂SO₄. The solvent was removed in vacuum, concentrated and subjectedfor chromatographic separation. The eluent was allowed to come in asolution of pet ether:EtOAC=90:10 as a pale yellow liquid [α]²⁵=+23.22(c 1.24, CHCl₃); 1H NMR (200 MHz, CDCl3): δ 6.69-6.80 (dd, 1H), 5.96 (d,1H), 4.57 (m, 2H), 4.14 (m, 3H), 3.81 (m, 1H), 1.40 (t, 3H), 1.23 (d,2H), 0.84 (s, 9H), −0.4 (s, 6H); 13C NMR (CDCl3, 50 MHz): 166.04,147.76, 121.95, 94.48, 75.04, 68.07, 60.37, 55.55, 34.94, 30.78, 25.92,23.85, 18.12, 14.28, −4.29, −4.67.

Example 35: Stagonolide C

Me₃SiBr (0.8 ml, 0.45 mmol) was added dropwise to a cold (−40° C.)stirred solution of 21 (43 mg, 0.15 mmol) in CH₂Cl₂ (50 ml). The mixturewas stirred at −40° C. for 2 h. After the completion of reaction(monitored by TLC), the reaction mixture was poured into saturated aq.NaHCO₃ solution, and extracted with CH₂Cl₂. The organic layer was driedover anhydrous Na₂SO₄, and concentrated under reduced pressure to givethe crude product. The residue was then purified with columnchromatography using petroleum ether: EtOAc (6:4 v/v) to givestagonolide C (20 mg) as a colorless liquid.

Yield: 76%; [α]_(D) ²⁵+44.7 (c 0.9, CHCl₃); {lit.^(4d)[α]_(D) ²⁵+45.6 (c1.0, CHCl₃)}; IR (CHCl₃): υ_(max) 3385, 2926, 2850, 1720, 1445, 1370,1098, 1235, 1110, 1040 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 1.24 (d, J=6.8Hz, 3H), 1.72-1.96 (m, 2H), 1.99-2.10 (m, 3H), 2.20-2.34 (m, 1H),4.02-4.14 (m, 2H), 5.06-5.20 (m, 1H), 5.41 (dd, J=8.9, 15.8 Hz, 1H),5.56 (dd, J=9.0, 16.1 Hz, 1H); ¹³C NMR (50 MHz, CDCl₃): δ 22.0, 31.5,34.4, 43.3, 67.4, 72.1, 74.5, 132.9, 174.0; Anal. Calcd for C₁₀H₁₆O₄requires C, 59.98; H, 8.05. found C, 60.03; H, 8.12%.

Example 36: Aspinolide A

To a well stirred solution of silyl ether 28 (200 mg, 0.48 mmol) in dryTHF (5 mL) was added 1 M solution of tetrabutylammonium fluoride (1 mL,1 mmol) at 0° C. The reaction mixture was stirred at this temperaturefor additional 2 h. After the completion of reaction (monitored by TLC),it was quenched with H₂O (1 mL) and the reaction mixture extracted withEt₂O (3×20 mL). then washed with brine, dried over anhydrous Na₂SO₄.After the removal of solvent, the crude product was dissolved in freshlydistilled degassed anhydrous CH₂Cl₂ (50 mL). The reaction mixture wastreated with Grubb's II catalyst (82 mg, 20 mol %) and heated at refluxfor 24 h under inert atmosphere. After the completion of reaction(monitored by TLC), the solvent was then distilled off and the residuewas purified by column chromatography with petroleum ether/EtOAc (9:1v/v) to afford 2 (54 mg) as a viscous liquid.

Yield: 69%; [α]_(D) ²⁵ −40.7 (c 0.3, MeOH) {lit.^(4e) [α]_(D) ²⁵ −41.6(c 0.25, MeOH)}; IR (CHCl₃): υ_(max) 3436, 2920, 2852, 1730, 970, 1460,1275 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 1.29 (d, J=6.1 Hz, 3H), 1.52-1.89(m, 4H), 2.30 (t, J=7.1 Hz, 2H), 2.40-2.42 (m, 2H), 3.97-4.06 (m, 1H),5.02-5.07 (m, 1H), 5.23 (d, J=7.6 Hz, 1H), 5.59-5.72 (m, 1H); ¹³C NMR(50 MHz, CDCl₃): δ 19.7, 22.3, 35.5, 38.6, 42.1, 71.8, 74.6, 131.7,137.4, 176.5; Analysis: C₁₀H₁₆O₃ requires C, 65.19; H, 8.75. found C,65.11; H, 8.86.

Example 37: Compound 15 (R)-3-(tert-butyldimethylsilyloxy)pent-4-enoicacid, 14

To a solution of alcohol (15.0 g) in CH₃CN/H₂O (4:1) was added in oneportion bis-acetoxy iodobenzene (24.34, 75.6 mmol) and TEMPO (1.07 g,6.9 mmol). The reaction mixture was then allowed to stir at 25° C. for 4h. After completion of reaction (monitored by TLC), the reaction mixturewas quenched by addition of saturated solution of aq.ammoniumthiosulphate. The organic layer was separated, washed with brineand subjected to column chromatographic purification with petroleumether/EtOAc (9:1 v/v) to afford the acid 15.

Yield: 80%; [α]_(D) ²⁵ −6.5 (c 1.0, CHCl₃); IR (CHCl₃): 3444, 3070,2931, 2858, 1707, 1462, 1425, 1257, 1109 cm⁻¹; ¹H NMR (200 MHz, CDCl₃):δ 0.03 (s, 3H), 0.05 (s, 3H), 0.89 (s, 9H), 1.47-1.76 (m, 4H), 2.32-2.39(t, J=6.10 Hz, 2H), 4.07-4.15 (m, 1H), 5.01-5.19 (m, 2H), 5.69-5.86 (m,1H); ¹³C NMR (50 MHz, CDCl₃): δ −4.92, −4.43, 18.17, 20.22, 25.82,29.64, 33.96, 37.08, 73.28, 113.94, 141.19, 179.90; Anal. Calcd forC₁₁H₂₂O₃Si requires C, 57.35; H, 9.63. found C, 57.45; H, 9.68%.

Advantages of Invention

Thus the present invention provides cost effective, non-toxic improvedprocess for asymmetric synthesis of highly enantioselective decanolidesin good yield from cheaper, non-chiral, easily available startingmaterial.

The naturally available proline based catalyst is used for introductionof chirality that enhances the enantioselectivity of the desireddecanolides and makes the process environmental friendly. Further byavoiding expensive and toxic metal catalyst present inventors haveimproved upon the economics of the process. Also, the present processimproves the overall yield by reducing lengthy process steps.

We claim:
 1. An organo catalytic process for the preparation ofdecanolides of Formula Ic

wherein the said process comprising the steps of: i) allylboration ofaldehyde (1)

 in presence of allyldiisopinocamphenylborane at temperature in therange of −120° C. to −80° C. for 1-2 hours in non-polar organic solventsselected from the group consisting of diethyl ether, pentane,cyclopentane, benzene, toluene, 1,4-dioxane, chloroform, and mixturesthereof followed by treatment with NaOH and aqueous H₂O₂ to obtainchiral allylic alcohol (3)

ii) esterification of allylic alcohol (3) with butyldimethylsilyl(TBS)protected carboxylic acid (15)

 in presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride, 4-dimethylaminopyridine in DCM at temperature range 0° to30° C. for 5 to 8 hours with subsequent deprotection of TBS in presenceof tetra-n-butylammonium fluoride in THF for 6-8 hours yields allylicalcohol (17)

and iii) ring closing metathesis reaction of compound (17) in presenceof Grubbs II catalyst (5 to 15%) in dry CH₂Cl₂ for 18-24 hours to obtaindecanolides of Formula Ic.